Clinically diagnosed pneumonia in children aged 2-59 months is a leading cause of pediatric hospitalizations and is associated with significant childhood morbidity and mortality. The etiology is usually bacterial or viral. Although optimal treatment of pneumonia requires promptly detecting a bacterial infection, there is no accurate method to yield rapid point-of-care diagnosis. Antibiotic therapy is frequently overprescribed as a result of suspected bacterial infections resulting in development of antibiotic resistance. Conversely, concomitant bacterial and viral pneumonias in patients with malarial infections are common and withholding antibiotic therapy from patients with bacterial infections may occur. In a preliminary study carried out in Mozambique, we identified a combination of blood proteins (biosignature) with 96% sensitivity and 86% specificity for detecting bacterial disease. We screened through a large panel of markers and used different approaches to select and combine markers. The current project aims to not only validate the previously identified biosignature but also to improve upon it by searching through additional markers in patients with clinical pneumonia. Our goal is to describe combinations of a limited number of proteins highly sensitivity to detect bacterial disease, with large specificity, precision, and reproducibility. Furthermore, we will seek to validate in a resource-limited setting a biosignature previously identified as accurate by an European consortium and to explore biosignatures to prognosticate clinical pneumonia that can guide decisions about patient referral to higher level care. We will test our approach in a randomized trial funded by the Bill and Melinda Gates Foundation and conducted in the Medical Research Council Unity The Gambia (MRCG) aiming to evaluate alternative vaccination schedules of the 13-valent pneumococcal conjugate vaccine. Patients will be classified using a definitive diagnosis criterion (based on a standard battery of tests including bacterial, malarial, and viral laboratory tests and chest radiographs) and a probable diagnosis criterion (based on clinical and radiographic evaluation). We will measure proteins at admission using multiplex bead Luminex-based immunoassays that include novel and known markers in 90 children with definitive and 160 children with probable established diagnosis for the clinical pneumonia. Through data mining methods, we will combine markers that may have moderate sensitivity and specificity on their own but have improved accuracy when used in combination. Results of this study may ultimately support future development of an accurate point-of-care test for bacterial disease to guide clinicians in choices of treatment, hence reducing over/under use of antibiotic therapy, particularly in resource-limited areas. Moreover, this study shall propose a combination of proteins that, if validated, can assist decisions about prioritization of intensive care in resource-limited settings where it is critically important to optimize utilization of available resources.